Serotonin gene polymorphisms and bipolar I disorder: Focus on the serotonin transporter

Hader A. Mansour; Michael E. Talkowski; Joel Wood; Lora Pless; Mikhil Bamne; Kodavali V. Chowdari; Michael Allen; Charles L. Bowden; Joseph Calabrese; Rif S. El-Mallakh; Andrea Fagiolini; Stephen V. Faraone; Mark D. Fossey; Edward S. Friedman; Laszlo Gyulai; Peter Hauser; Terence A. Ketter; Jennifer M. Loftis; Lauren B. Marangell; David J. Miklowitz; Andrew A. Nierenberg; Jayendra Patel; Gary S. Sachs; Pamela Sklar; Jordan W. Smoller; Michael E. Thase; Ellen Frank; David J. Kupfer; Vishwajit L. Nimgaonkar

doi:10.1080/07853890500357428

Serotonin gene polymorphisms and bipolar I disorder: Focus on the serotonin transporter

Hader A. Mansour, Michael E. Talkowski, Joel Wood, Lora Pless, Mikhil Bamne, Kodavali V. Chowdari, Michael Allen, Charles L. Bowden, Joseph Calabrese, Rif S. El-Mallakh, Andrea Fagiolini, Stephen V. Faraone, Mark D. Fossey, Edward S. Friedman, Laszlo Gyulai, Peter Hauser, Terence A. Ketter, Jennifer M. Loftis, Lauren B. Marangell, David J. MiklowitzAndrew A. Nierenberg, Jayendra Patel, Gary S. Sachs, Pamela Sklar, Jordan W. Smoller, Michael E. Thase, Ellen Frank, David J. Kupfer, Vishwajit L. Nimgaonkar

Psychiatry

Research output: Contribution to journal › Review article › peer-review

40 Scopus citations

Abstract

The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1-q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case-control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n=182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case-control or family-based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub-groups of BDI are worthwhile.

Original language	English (US)
Pages (from-to)	590-602
Number of pages	13
Journal	Annals of Medicine
Volume	37
Issue number	8
DOIs	https://doi.org/10.1080/07853890500357428
State	Published - Dec 2005

Keywords

Association
Bipolar disorder
Genetic
Polymorphism
Serotonin
Serotonin transporter

ASJC Scopus subject areas

General Medicine

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10.1080/07853890500357428

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Mansour, H. A., Talkowski, M. E., Wood, J., Pless, L., Bamne, M., Chowdari, K. V., Allen, M., Bowden, C. L., Calabrese, J., El-Mallakh, R. S., Fagiolini, A., Faraone, S. V., Fossey, M. D., Friedman, E. S., Gyulai, L., Hauser, P., Ketter, T. A., Loftis, J. M., Marangell, L. B., ... Nimgaonkar, V. L. (2005). Serotonin gene polymorphisms and bipolar I disorder: Focus on the serotonin transporter. Annals of Medicine, 37(8), 590-602. https://doi.org/10.1080/07853890500357428

Mansour, HA, Talkowski, ME, Wood, J, Pless, L, Bamne, M, Chowdari, KV, Allen, M, Bowden, CL, Calabrese, J, El-Mallakh, RS, Fagiolini, A, Faraone, SV, Fossey, MD, Friedman, ES, Gyulai, L, Hauser, P, Ketter, TA, Loftis, JM, Marangell, LB, Miklowitz, DJ, Nierenberg, AA, Patel, J, Sachs, GS, Sklar, P, Smoller, JW, Thase, ME, Frank, E, Kupfer, DJ & Nimgaonkar, VL 2005, 'Serotonin gene polymorphisms and bipolar I disorder: Focus on the serotonin transporter', Annals of Medicine, vol. 37, no. 8, pp. 590-602. https://doi.org/10.1080/07853890500357428

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title = "Serotonin gene polymorphisms and bipolar I disorder: Focus on the serotonin transporter",

abstract = "The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1-q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case-control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n=182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case-control or family-based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub-groups of BDI are worthwhile.",

keywords = "Association, Bipolar disorder, Genetic, Polymorphism, Serotonin, Serotonin transporter",

author = "Mansour, {Hader A.} and Talkowski, {Michael E.} and Joel Wood and Lora Pless and Mikhil Bamne and Chowdari, {Kodavali V.} and Michael Allen and Bowden, {Charles L.} and Joseph Calabrese and El-Mallakh, {Rif S.} and Andrea Fagiolini and Faraone, {Stephen V.} and Fossey, {Mark D.} and Friedman, {Edward S.} and Laszlo Gyulai and Peter Hauser and Ketter, {Terence A.} and Loftis, {Jennifer M.} and Marangell, {Lauren B.} and Miklowitz, {David J.} and Nierenberg, {Andrew A.} and Jayendra Patel and Sachs, {Gary S.} and Pamela Sklar and Smoller, {Jordan W.} and Thase, {Michael E.} and Ellen Frank and Kupfer, {David J.} and Nimgaonkar, {Vishwajit L.}",

note = "Funding Information: We gratefully acknowledge statistical advice from Dr Bernie Devlin and Mr Vibhor Sonpal. We thank Ms Amber Johnson for technical assistance. Supported in part by grants from the National Institutes of Health (MH63420, MH56242 and MH66263 to VLN) and the Mental Health Intervention Research Center (# MH 30915 to DJK).",

year = "2005",

month = dec,

doi = "10.1080/07853890500357428",

language = "English (US)",

volume = "37",

pages = "590--602",

journal = "Annals of Medicine",

issn = "0785-3890",

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TY - JOUR

T1 - Serotonin gene polymorphisms and bipolar I disorder

T2 - Focus on the serotonin transporter

AU - Mansour, Hader A.

AU - Talkowski, Michael E.

AU - Wood, Joel

AU - Pless, Lora

AU - Bamne, Mikhil

AU - Chowdari, Kodavali V.

AU - Allen, Michael

AU - Bowden, Charles L.

AU - Calabrese, Joseph

AU - El-Mallakh, Rif S.

AU - Fagiolini, Andrea

AU - Faraone, Stephen V.

AU - Fossey, Mark D.

AU - Friedman, Edward S.

AU - Gyulai, Laszlo

AU - Hauser, Peter

AU - Ketter, Terence A.

AU - Loftis, Jennifer M.

AU - Marangell, Lauren B.

AU - Miklowitz, David J.

AU - Nierenberg, Andrew A.

AU - Patel, Jayendra

AU - Sachs, Gary S.

AU - Sklar, Pamela

AU - Smoller, Jordan W.

AU - Thase, Michael E.

AU - Frank, Ellen

AU - Kupfer, David J.

AU - Nimgaonkar, Vishwajit L.

N1 - Funding Information: We gratefully acknowledge statistical advice from Dr Bernie Devlin and Mr Vibhor Sonpal. We thank Ms Amber Johnson for technical assistance. Supported in part by grants from the National Institutes of Health (MH63420, MH56242 and MH66263 to VLN) and the Mental Health Intervention Research Center (# MH 30915 to DJK).

PY - 2005/12

Y1 - 2005/12

N2 - The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1-q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case-control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n=182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case-control or family-based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub-groups of BDI are worthwhile.

AB - The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1-q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case-control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n=182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case-control or family-based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub-groups of BDI are worthwhile.

KW - Association

KW - Bipolar disorder

KW - Genetic

KW - Polymorphism

KW - Serotonin

KW - Serotonin transporter

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U2 - 10.1080/07853890500357428

DO - 10.1080/07853890500357428

M3 - Review article

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AN - SCOPUS:28844469295

SN - 0785-3890

VL - 37

SP - 590

EP - 602

JO - Annals of Medicine

JF - Annals of Medicine

IS - 8

ER -

Serotonin gene polymorphisms and bipolar I disorder: Focus on the serotonin transporter

Abstract

Keywords

ASJC Scopus subject areas

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